Month: April 2022

We often encounter nonlinear dynamical systems that behave unpredictably, such as the earth’s climate and the stock market. To analyze them, measurements taken over time are used to reconstruct the state of the system. However, this depends on the quality of the data. Now, researchers from Japan have proposed an all-new method for determining the necessary parameters that results in an accurate reconstruction. Their new technique has far-reaching implications for the field of data science.

Many frequently observed real-world phenomena are nonlinear in nature. This means that their output does not change in a manner that is proportional to their input. These models have a degree of unpredictability, where it is unclear how the system will respond to any changes in its input. This is especially important in the case of dynamical systems, where the output of the model changes with time. For such systems, the time series data, or the measurements from the system over time, have to be analyzed to determine how the system changes or evolves with time.

Due to the commonality of the problem, many solutions have been proposed to analyze time-series data to gain an understanding of the system. One method of reconstructing the state of a system based on time series data is state space reconstruction, which can be used to reconstruct those states where the system remains stable or unchanged with time. Such states are known as “attractors.” However, the accuracy of the reconstructed attractors depends on the parameters used for reconstruction, and due to the finite nature of the data, such parameters are difficult to ascertain, resulting in inaccurate reconstructions.

Now, in a new study to be published on April 1, 2022, in Nonlinear Theory and Its Applications, IEICE, Professor Tohru Ikeguchi from Tokyo University of Science, his PhD student Mr. Kazuya Sawada from Tokyo University of Science, and Prof. Yutaka Shimada from Saitama University, Japan, have used the geometric structure of the attractor to estimate the reconstruction parameters.

“To reconstruct the state space using time-delay coordinate systems, two parameters, the dimension of the state space and the delay time, must be set appropriately, which is an important issue that is still being actively studied in this field. We discuss how to set these parameters optimally by focusing on the geometric structure of the attractor as one way to solve this problem,” explains Prof. Ikeguchi.

To obtain the optimal values of the parameters, the researchers used five three-dimensional nonlinear dynamical systems and maximized the similarity of the inter-point distance distributions between the reconstructed attractor and the original attractor. As a result, the parameters were obtained in a way that produced a reconstructed attractor which was geometrically as close as possible to the original.

While the method was able to generate the appropriate reconstruction parameters, the researchers did not factor in the noise that is normally encountered in real-world data, which can significantly affect the reconstruction. “Mathematically, this method has been proven to be a good one, but there are many considerations that need to be made before applying this method to real-world data analysis. This is because real-world data contains noise, and the length and accuracy of the observed data is finite,” explains Prof. Ikeguchi.

Despite this, the method resolves one of the limitations involved in determining the state of nonlinear dynamical systems that are encountered in various fields of science, economics, and engineering. “This research has yielded an important analysis technique in the current data science field, and we believe that it is important for handling a wide variety of data in the real world,” concludes Prof. Ikeguchi.

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Reference

Title of original paper: Similarities of inter-point distance distributions on original and

reconstructed attractors

Journal: Nonlinear Theory and Its Applications, IEICE

DOI: https://doi.org/10.1587/nolta.13.385

About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan’s development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society”, TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today’s most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

Website: https://www.tus.ac.jp/en/mediarelations/

About Professor Tohru Ikeguchi from Tokyo University of Science

Tohru Ikeguchi received M.E. and Ph.D degrees from Tokyo University of Science, Japan. After working for nearly a decade as Full Professor at Saitama University, Japan, he worked at Tokyo University of Science as Full Professor at the Department of Management Science from 2014 to 2016. Since then, he has been a Full Professor at the Department of Information and Computer Technology in Tokyo University of Science. His research interests include nonlinear time series analysis, computational neuroscience, application of chaotic dynamics to solving combinatorial optimization problems, and complex network theory. He has published over 230 papers and proceedings.

A new study found that disulfiram, a drug used to treat chronic alcoholism, can safely reduce anxiety levels in rodents.

Disulfiram is a drug used to treat chronic alcoholism. However, studies suggest that it also inhibits chemokine receptor signaling pathways that are associated with the regulation of anxiety in rodents. Now, a team of researchers from the Tokyo University of Science show that disulfiram can effectively reduce anxiety without causing any of the adverse effects that are linked to other anxiolytic drugs. Thus, disulfiram could potentially become a safe and effective anti-anxiety drug.

Alcoholism, if left untreated, could have dangerous repercussions. Thus, it is no surprise that there are a range of drugs developed to treat this condition. Of these drugs, disulfiram (DSF) is approved by the Food and Drug Agency (FDA) for the treatment of alcoholism. DSF primarily inhibits the enzyme aldehyde dehydrogenase (ALDH), which is responsible for the metabolism of alcohol.

Could the inhibitory effects of DSF extend to signaling molecules as well?

According to recent studies, DSF in fact inhibits a cytoplasmic protein known as FROUNT, which controls the direction in which certain immune cells migrate. DSF blocks FROUNT from interacting with two chemokine receptors known as CCR2 and CCR5, which are involved in important cellular signaling pathways.

A few studies suggest that chemokine receptors may be involved in the regulation of emotional behaviors in rodents. However, there is a lack of data on the exact association between FROUNT-chemokine signaling and DSF. To clarify this link, a team comprising Prof. Akiyoshi Saitoh from Tokyo University of Science and other researchers from institutes across Japan conducted a study examining the pharmacological properties of DSF. The study, which was published online on March 7, 2022 in Frontiers in Pharmacology, describes how the research team used an elevated plus-maze (EPM) test—which is used to screen for anxiolytic drugs—to study the effects of DSF in mice.

The EPM apparatus consists of four arms set in a cross pattern, connected to a central square. Two arms are protected by vertical boundaries, whereas two have unprotected edges. Usually, mice with anxiety prefer to spend time in the closed arms.

In this case, some mice were administered diazepam (a drug commonly used to treat anxiety) and others, DSF. These mice were then placed in the EPM apparatus, and their activity was monitored. To their surprise, the team found that mice treated with DSF spent significantly more time in the open arms of the apparatus, which indicates that they were less anxious. The team also tested the anxiolytic effects of a more potent FROUNT inhibitor, known as DSF-41, and observed similar results.

What’s interesting is that these behavioral changes were similar to those observed in mice treated with diazepam. How exactly did DSF achieve this?

The team had previously discovered that increased extracellular glutamate (which is an important amino acid and neurotransmitter) levels are associated with increased anxiety in mice.

“We propose that DSF inhibits FROUNT protein and the chemokine signaling pathways under its influence, which may suppress presynaptic glutamatergic transmission in the brain,” says Prof. Saitoh. “This, in turn, attenuates the levels of glutamate in the brain, reducing overall anxiety.”

The team was also pleasantly surprised to find that in contrast with diazepam, DSF treatment did not lead to adverse effects such as amnesia, coordination disorders, or sedation.

According to Prof. Saitoh, “These results indicate that DSF can be used safely by elderly patients suffering from anxiety and insomnia and has the potential to become a breakthrough psychotropic drug.”

What are the long-term implications of these results? Dr. Saitoh explains, “We plan to further clarify how DSF exerts its pharmaceutical actions. Hopefully, we will also be able to elucidate the exact role of the FROUNT molecule in the central nervous system.”

This is one of the first studies to reveal that DSF exhibits anti-anxiety properties comparable to those of existing benzodiazepines without exhibiting any side effects observed with benzodiazepines. Hopefully, DSF’s inhibitory activity against FROUNT functioning could be explored for successful anxiolytic drug development.

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Reference

Title of original paper: Disulfiram Produces Potent Anxiolytic-Like Effects Without Benzodiazepine Anxiolytics-Related Adverse Effects in Mice

Journal: Frontiers in Pharmacology

DOI: https://doi.org/10.3389/fphar.2022.826783

About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan’s development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society”, TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today’s most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

Website: https://www.tus.ac.jp/en/mediarelations/

About Prof. Akiyoshi Saitoh from Tokyo University of Science

Dr. Akiyoshi Saitoh is a Professor at the Faculty of Pharmaceutical Sciences, Tokyo University of Science. He is a senior researcher with more than 20 years of experience in the fields of medicinal pharmacology, behavioral pharmacology, and neuroscience. His research also focuses on the role of the amygdala in the extinction of fear memory in rodents, and the development of a novel opioid delta receptor agonist for antidepressants/anxiolytics. Dr. Saitoh has contributed to more than 100 research publications and is the first author of this study.

Funding information

This study was partially supported by the Tsukuba Clinical Research and Development Organization (T-CReDO) from the Japan Agency for Medical Research and Development (AMED).

Fearful events negatively impact the brain. For instance, war veterans often go through post-traumatic stress disorder months after the cessation of the triggering event. Now, in a study led by Tokyo University of Science researchers, the precise mechanism of suppression of such fearful memories has been uncovered. Using a mouse model, the researchers identified the associated biochemical pathways, thus paving the way for the development and clinical evaluation of therapeutic compounds such as KNT-127.

Tragic events like wars, famines, earthquakes, and accidents create fearful memories in our brain. These memories continue to haunt us even after the actual event has passed. Luckily, researchers from Tokyo University of Science (TUS) have recently been able to understand the hidden biochemical mechanisms involved in the selective suppression of fearful memories, which is called fear extinction. The researchers, who had previously demonstrated fear extinction in mice using the chemically synthesized compound “KNT-127,” have now identified the underlying mechanism of this compound’s action. Their findings have been published recently in Frontiers in Behavioral Neuroscience.

Prof. Akiyoshi Saitoh, lead author of the study, and Professor at TUS, muses, “Drugs that treat fear-related diseases like anxiety and posttraumatic stress disorder must be able to help extinguish fear. We previously reported that KNT-127, a selective agonist of the d-opioid receptor or DOP, facilitates contextual fear extinction in mice. However, its site of action in the brain and the underlying molecular mechanism remained elusive. We therefore investigated brain regions and cellular signaling pathways that we assumed would mediate the action of KNT-127 on fear extinction.”

“We investigated the molecular mechanism of KNT-127-mediated suppression of fearful memories. We administered KNT-127 to specific brain regions and identified the brain regions involved in promoting fear extinction via delta receptor activation,” elaborates Dr. Daisuke Yamada, co-author of the study, and Assistant Professor at TUS.

Using a mouse model, the research team performed fear conditioning test on laboratory mice. During fear conditioning, mice learn to associate a particular neutral conditioned stimulus with an aversive unconditioned stimulus (e.g., a mild electrical shock to the foot) and show a conditioned fear response (e.g., freezing).

After the initial fear conditioning, the mice were re-exposed to the conditioning chamber for six minutes as part of the extinction training. Meanwhile, the fear-suppressing therapeutic “KNT-127” was microinjected into various regions of the brain, 30 minutes prior to re-exposure. The treated brain regions included the basolateral nucleus of the amygdala (BLA), the hippocampus (HPC), and the prelimbic (PL) or infralimbic subregions (IL) of the medial prefrontal cortex. The following day, the treated mice were re-exposed to the chamber for six minutes for memory testing. The fear-suppressing “KNT-127” that infused into the BLA and IL, but not HPC or PL, significantly reduced the freezing response during re-exposure. Such an effect was not observed in mice that did not receive the KNT-127 treatment, thus confirming the fear-suppressing potential of this novel compound.

Chemical compounds known to inhibit the actions of key intracellular signaling pathways like PI3K/Akt and MEK/ERK pathways reversed the therapeutic effect, thereby suggesting the key roles of these two pathways in influencing KNT-127-mediated fear extinction.

The first author of the study, Ayako Kawaminami, who is currently pursuing research at TUS, says, “The selective DOP antagonist that we used for pretreatment antagonized the effect of KNT-127 administered into the BLA and IL. Further, local administration of MEK/ERK inhibitor into the BLA and of PI3K/Akt inhibitor into the IL abolished the effect of KNT-127. These findings strongly indicated that the effect of KNT-127 is mediated by MEK/ERK signaling in the BLA, by PI3K/Akt signaling in the IL, and by DOPs in both brain regions. We have managed to show that DOPs play a role in fear extinction via distinct signaling pathways in the BLA and IL.”

PTSD and phobias are thought to be caused by the inappropriate or inadequate control of fear memories. Currently, serotonin reuptake inhibitors and benzodiazepines are prescribed during therapy. However, many patients do not derive significant therapeutic benefits from these drugs. Therefore, there is an urgent need for the development of new therapeutic agents that have a different mechanism of action from existing drugs.

Dr. Hiroshi Nagase, a Professor at University of Tsukuba and a coauthor of the study, concludes, “We have succeeded in creating KNT-127 by successfully separating convulsion- and catalepsy-inducing actions, which has so far been extremely difficult. Our findings will provide useful and important information for the development of evidence-based therapeutics with a new mechanism of action, that is targeting DOP.”

Fighting fear with the right therapeutic is the need of the hour, as anxiety and stress increase globally, and the findings of this study could help us achieve this objective. We have our fingers crossed.

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Reference

Title of original paper: Selective δ-Opioid Receptor Agonist, KNT-127, Facilitates Contextual Fear Extinction via Infralimbic Cortex and Amygdala in Mice

Journal: Frontiers in Behavioral Neuroscience

DOI: https://doi.org/10.3389/fnbeh.2022.808232

About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan’s development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society”, TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today’s most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

Website: https://www.tus.ac.jp/en/mediarelations/

About Professor Akiyoshi Saitoh from Tokyo University of Science

Dr. Akiyoshi Saitoh is serving as a Professor in the Department of Pharmacy, at the Tokyo University of Science, Japan. His research work primarily focuses on the role of the amygdala in the rodent fear extinction memory as well as on the development of novel opioid delta receptor agonists for combating depression and anxiety. Prof. Saitoh has published over 100 refereed papers so far. He also has a patent to his credit.